Implantable materials having engineered surfaces and method of making same

ABSTRACT

An implantable biocompatible material includes one or more vacuum deposited layers of biocompatible materials deposited upon a biocompatible base material. At least a top most vacuum deposited layer includes a homogeneous molecular pattern of distribution along the surface thereof and comprises a patterned array of geometric physiologically functional features.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/107,510, filed May 13, 2011, which is a continuation-in-part of U.S.patent application Ser. No. 12/428,981, filed Apr. 23, 2009, now U.S.Pat. No. 8,268,340, and is a continuation-in-part of U.S. patentapplication Ser. No. 11/091,669, filed on Mar. 28, 2005, now U.S. Pat.No. 8,147,859; and claims the benefit of priority to PCT InternationalPatent Application No. PCT/US2003/30383, which bears an internationalfiling date of Sep. 26, 2003; which claims priority to U.S. ProvisionalPatent Application Ser. No. 60/414,031, filed Sep. 26, 2002, all hereinincorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

The present invention relates generally to implantable medical devicesand more particularly to controlling surface properties of implantablebiocompatible materials suitable for fabrication of implantable medicaldevices.

Implantable medical devices are fabricated of materials that aresub-optimal in terms of the biological response they elicit in vivo.Many conventional materials used to fabricate implantable devices, suchas titanium, polytetrafluoroethylene, silicone, carbon fiber andpolyester, are used because of their strength and physiologically inertcharacteristics. However, tissue integration onto these materials istypically slow and inadequate. Certain materials, such as silicone andpolyester, elicit a significant inflammatory, foreign body response thatdrives fibrous encapsulation of the synthetic material. The fibrousencapsulation may have significant adverse effects on the implant.Moreover, conventional biomaterials have proved inadequate in elicitinga sufficient healing response necessary for complete device integrationinto the body. For example, in devices that contact blood, such asstents and vascular grafts, attempts to modify such devices to promoteendothelial cell adhesion may have a concomitant effect of making thedevices more thrombogenic.

When implanted, conventional blood-contacting implantable devices, suchas stents, stent-grafts, grafts, valves, shunts and patches, fail todevelop a complete endothelial layer, thereby exposing the devicematerial to thrombus formation or smooth muscle cell proliferation, andultimate failure of the implanted device. It has been recognized that,when implanted into the body, metals are generally considered to havesuperior biocompatibility than polymers used to fabricate commerciallyavailable polymeric grafts.

In cellular interactions with prosthetic material surfaces, celladhesion to the material surface is mediated by integrins present oncell membranes that interact with the prosthetic surface. Integrins arethe most prominent member of a class of extracellular matrix (ECM)adhesion receptors. Integrins are a large family of heterodimerictransmembrane proteins with different α and β subunits. Integrins areregulated at several levels. Modulation of the affinity of the adhesionreceptor for ligand, termed affinity modulation, is a mechanism foractivation of platelet aggregation and is believed to underlieactivation of leukocyte adhesion. Adhesive strengthening by clusteringof adhesion receptors or by cytoskeletal-dependent processes such ascell spreading has been shown to be crucial for strong cellularattachment, control of cell growth and cell motility. Under high shearforces present in flowing blood, leukocytes first tether, then rollalong the vessel surface. When a local signal, e.g., a cytokine, isreleased in their vicinity, the leukocyte arrests, develops a firmadhesion then migrates across the endothelium. Tethering, rolling,arrest and adhesion tightening are all known to result from activationof leukocyte integrins.

Once adhered to a surface, cell spreading and migration are associatedwith assembly of focal adhesion junctions. Cell migration entails thecoordination of cytoskeletal-mediated process extension, i.e., filopodiaand lamellopodia, formation of adhesive contacts at the leading edge ofa cell, breaking adhesive contacts, and cytoskeletal retraction at thetrailing edge of the cell. Focal adhesions are comprised of integrins asthe major adhesion receptors along with associated cytoplasmic plaqueproteins. Assembly of focal adhesions is regulated by extracellularligand binding events and by intracellular signaling events. Ligandbinding controls localization of β1- and β3-containing integrins intofocal adhesions. The cytoplasmic domains of the β subunits haveintrinsic signals for focal adhesion localization, but incorporation ofthe integrins into focal adhesions is prevented by the α subunits of theheterodimers. Ligand binding, however, relieves this inhibition andallows the subunit cytoplasmic tail signals to recruit the integrindimmer into the focal adhesion.

Attempts at coating implanted metal devices, such as stents, withproteins that contain the Arg-Gly-Asp (RGD) attachment site have beenmade with some success. The RGD sequence is the cell attachment site ofa large number of adhesive extracellular matrix, blood, and cell surfaceproteins and many of the known integrins recognize the RGD sequence intheir adhesion protein ligands. Integrin-binding activity may also bereproduced by synthetic peptides containing the RGD sequence. However,bare metal implanted materials will not, of course, have native RGDattachment sites. Thus, metal implantable devices, such as stents, havebeen derivitized with polymers having RGD attachment sites bound to thepolymer matrix.

When prosthetic materials are implanted, integrin receptors on cellsurfaces interact with the prosthetic surface. When cells come intocontact with the extracellular matrix, such as a prosthetic surface,their usual response is to extend filopodia, and integrins at the tip ofthe filopodia bind to the extracellular matrix and initiate theformation of focal adhesions. Actin-rich lamellipodia are generated,often between filopodia, as the cell spreads on the extracellularmatrix. Fully developed focal adhesions and associated actin stressfibers ensue. These same evens occur during cell migration as cellsextend lamellipodia and form focal adhesions to derive the tractionnecessary for movement. Giancotti, F. G., et al. Science, 285:13 August1999, 1028-1032.

The integrin receptors are specific for certain ligands in vivo. If aspecific protein is adsorbed on a prosthetic surface and the ligandexposed, cellular binding to the prosthetic surface may occur byintegrin-ligand docking. It has also been observed that proteins bind tometals in a more permanent fashion than they do to polymers, therebyproviding a more stable adhesive surface. The conformation of proteinscoupled to surfaces of most medical metals and alloys appears to exposegreater numbers of ligands and attract endothelial cells having surfaceintegrin clusters to the metal or alloy surface, preferentially overleukocytes.

Because of their greater adhesive surface profiles, metals are alsosusceptible to short-term platelet activity and/or thrombogenicity.These deleterious properties may be offset by administration ofpharmacologically active antithrombogenic agents in routine use today.Surface thrombogenicity usually disappears 1-3 weeks after initialexposure. Antithrombotic coverage is routinely provided during thisperiod of time for coronary stenting. In non-vascular applications suchas musculoskeletal and dental, metals have also greater tissuecompatibility than polymers because of similar molecular considerations.The best article to demonstrate the fact that all polymers are inferiorto metals is van der Giessen, W J. et al. Marked inflammatory sequelaeto implantation of biodegradable and non-biodegradable polymers inporcine coronary arteries, Circulation, 1996:94(7):1690-7.

Normally, endothelial cells (EC) migrate and proliferate to coverdenuded areas until confluence is achieved. Migration, quantitativelymore important than proliferation, proceeds under normal blood flowroughly at a rate of 25 μm/hr or about 2.5 times the diameter of an EC,which is nominally 10 μm. EC migrate by a rolling motion of the cellmembrane, coordinated by a complex system of intracellular filamentsattached to clusters of cell membrane integrin receptors, specificallyfocal contact points. The integrins within the focal contact sites areexpressed according to complex signaling mechanisms and eventuallycouple to specific amino acid sequences in substrate adhesion molecules.An EC has roughly 16-22% of its cell surface represented by integrinclusters. Davies, P. F., Robotewskyi A., Griem M. L. Endothelial celladhesion in real time. J. Clin. Invest. 1993; 91:2640-2652, Davies, P.F., Robotewski, A., Griem, M. L., Qualitiative studies of endothelialcell adhesion, J. Clin. Invest. 1994; 93:2031-2038. This is a dynamicprocess, which involves more than 50% remodeling in 30 minutes. Thefocal adhesion contacts vary in size and distribution, but 80% of themmeasure less than 6 μm², with the majority of them being about 1 μm²,and tend to elongate in the direction of flow and concentrate at leadingedges of the cell. Although the process of recognition and signaling todetermine specific attachment receptor response to attachment sites isnot completely understood, availability of attachment sites willfavorably influence attachment and migration. Materials commonly used asmedical grafts, such as polymers, do not become covered with EC andtherefore do not heal after they are placed in the arteries.

There have been numerous attempts to increase endothelialization ofimplanted medical devices such as stents, including covering the stentwith a polymeric material (U.S. Pat. No. 5,897,911), imparting adiamond-like carbon coating onto the stent (U.S. Pat. No. 5,725,573),covalently binding hydrophobic moieties to a heparin molecule (U.S. Pat.No. 5,955,588), coating a stent with a layer of blue to black zirconiumoxide or zirconium nitride (U.S. Pat. No. 5,649,951), coating a stentwith a layer of turbostratic carbon (U.S. Pat. No. 5,387,247), coatingthe tissue-contacting surface of a stent with a thin layer of a Group VBmetal (U.S. Pat. No. 5,607,463), imparting a porous coating of titaniumor of a titanium alloy, such as Ti—Nb—Zr alloy, onto the surface of astent (U.S. Pat. No. 5,690,670), coating the stent, under ultrasonicconditions, with a synthetic or biological, active or inactive agent,such as heparin, endothelium derived growth factor, vascular growthfactors, silicone, polyurethane, or polytetrafluoroethylene (U.S. Pat.No. 5,891,507), coating a stent with a silane compound with vinylfunctionality, then forming a graft polymer by polymerization with thevinyl groups of the silane compound (U.S. Pat. No. 5,782,908), graftingmonomers, oligomers or polymers onto the surface of a stent usinginfrared radiation, microwave radiation or high voltage polymerizationto impart the property of the monomer, oligomer or polymer to the stent(U.S. Pat. No. 5,932,299). However, all these approaches do not addressthe lack of endothelialization of polymer grafts.

Overall rate to reach confluence for the endothelial cells on the bloodcontact surface of implanted medical device is mainly determined by twofactors, the rate of cell movement and rate of cell proliferation, withthe first being more important. The rate of cell movement furthercomprises three interrelated steps. Initially, a cell forms lamellipodiaand filopodia that protrude outward. This step involves reassembly ofactins in the forefront of lambaepolia. After protrusion of lamellipodiafrom one or multiple points from the cell membrane, the front end of thelamellipodia will form a close attachment, called focal adhesion point,to the substratum through the interaction of integrin on the cellmembrane and extracellular matrix binding site. The final step of cellmovement involves the contraction of the posterior end through theaction of myosin II. The formation of a focal adhesion point is criticalfor the cell movement because the protruding lamellipodia will otherwisefold back. Without the tension force from the focal adhesion point, acell loses the contraction from the posterior end and hence stopsmoving.

Availability of attachment sites on the substratum is not only importantfor the focal adhesion point formation, but also important forpropagation. It has been shown that cells are forced to spread, survivebetter and proliferate faster than cells that are confined to the sameamount of surface area (Science 276:1425-1428, 1997). This may explainwhy spreading of neighbor cells stimulate a cell to proliferate, aftercells are lost from epithelium.

The formation of extracellular matrix (ECM) is, to much extent,determined by the cells within it because molecules which form ECM aresecreted by the cells. Subsequently, the structure of the ECM, and hencethe distribution of attachment sites on the ECM for the integrinbinding, determines the focal adhesion point formation, the criticalstep in cell movement. Therefore, proper distribution of integrinbinding sites on the surface of an implanted medical devicesubstantially determines the speed of reendothelialization from the endssurrounding the device.

There still remains a need for a medical device that stimulatesendothelial proliferation and movement when implanted in order to forman endothelial layer over the medical device. Furthermore, there is aremaining need for a method of fabricating such a medical device.

SUMMARY OF THE INVENTION

In one embodiment, an implantable biocompatible material includes one ormore vacuum deposited layers of biocompatible materials deposited upon abiocompatible base material. At least a top most vacuum deposited layerincludes a homogeneous molecular pattern of distribution along thesurface thereof and comprises a patterned array of geometricphysiologically functional features.

In another embodiment, an implantable biocompatible material includes aplurality of layers of biocompatible materials formed upon one anotherinto a self-supporting multilayer structure. The plurality of layersincludes a vacuum deposited surface layer having a homogeneous molecularpattern of distribution along the surface thereof and comprises apatterned array of geometric physiologically functional features.

In a further embodiment, a method for making an implantablebiocompatible material is presented. The method includes the steps ofproviding an implantable biocompatible material having at least onesurface intended to contact tissue of body fluids in vivo and providinga mask having a defined pattern of openings corresponding in size andspacing to a predetermined distribution of binding domains to beimparted to the at least one surface.

The method further includes the steps of treating the at least onesurface of the biocompatible material through the mask by at least oneof three techniques. The first technique includes vacuum depositing alayer of material onto the at least one surface, wherein the vacuumdeposited layer is different from the at least one surface immediatelytherebeneath in a material property selected from the group of materialproperties consisting of: grain size, grain phase, grain materialcomposition, surface topography, and transition temperature, andremoving the mask to yield a plurality of binding domains defined on theat least one surface of the implantable, biocompatible material. Thesecond technique includes vacuum depositing a layer of sacrificialmaterial onto the at least one surface, removing the mask from the atleast one surface, vacuum depositing a second layer of material onto theat least one surface, wherein the second vacuum deposited layer isdifferent from the at least one surface immediately therebeneath in amaterial property selected from the group of material propertiesconsisting of: grain size, grain phase, grain material composition,surface topography, and transition temperature, and removing thesacrificial material to yield a plurality of binding domains defined onthe at least one surface of the implantable, biocompatible material. Thethird technique includes photo irradiating the at least one surface tophotochemically alter the at least one surface, and removing the mask toyield a plurality of binding domains defined on the at least one surfaceof the implantable, biocompatible material.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a perspective view of one embodiment including evenlydistributed elevated geometric physiologically functional features onthe surface of an implantable material.

FIG. 2 is cross-sectional view of FIG. 1 along line 2-2.

FIG. 3 is a perspective view of one embodiment including evenlydistributed chemically defined geometric physiologically functionalfeatures on the surface of an implantable material.

FIG. 4 is a cross-sectional view of FIG. 3 along line 4-4.

FIG. 5 is a photomicrograph showing one embodiment including geometricphysiologically functional features as carbon coated silicon.

FIGS. 6A-6C are photomicrographs showing cellular migration on thesurface with no inventive geometric physiologically functional featuresversus on the surface with inventive geometric physiologicallyfunctional features.

FIG. 7 is a photomicrograph showing the stained focal adhesion pointsclose to the geometric physiologically functional features.

FIGS. 8A-8B are photomicrographs showing the formation of multiple focaladhesion points of a migrating cell and its attachment to the inventivegeometric physiologically functional features.

FIGS. 9A-9D are cross-sectional diagrammatic views of one embodiment,the combination of a-d representing the steps to make an inventiveimplantable material with elevated geometric physiologically functionalfeatures.

FIGS. 10A-10D are cross-sectional diagrammatic views of one embodiment,the combination of a-d representing the steps to make an inventiveimplantable material with chemically defined geometric physiologicallyfunctional features.

FIG. 11A illustrates a cross-sectional view of layers of vacuumdeposited material; FIG. 11B illustrates a cross-sectional view of amask disposed over a surface of the layers of vacuum deposited materialof FIG. 11A; FIG. 11C illustrates a plan view of the mask of FIG. 11B;FIG. 11D illustrates a cross-sectional view of material deposited into aspace defined by holes of the mask of FIG. 11B; and FIG. 11E illustratesa cross-sectional view of geometric physiologically functional featurespatterned across the surface of FIG. 11B.

FIG. 12A illustrates a cross-sectional view of vacuum deposition of alayer of material onto a surface of layers of vacuum deposited materialand into a space defined by a sacrificial layer of material previouslydeposited onto the surface; and FIGS. 12B-12D illustrate across-sectional view of recessed geometric physiologically functionalfeatures.

FIG. 13A illustrates a cross-sectional view of layers of vacuumdeposited material deposited over a bulk material; and FIG. 13Billustrates recesses machined to various depths through a surface of thelayers of material.

FIG. 14 is a graph of the mean electrostatic force measurementscomparing 5 different metal surfaces; measurements were performed usinga 5 nm silicon nitride tip in the presence of a 0.01 M. NaCl medium atpH 7.4; force measurement values for each metal represent the mean ofdata from five different samples on which 5 sites were analyzed using 10measurements at each site; and mean values were compared using Student'sunpaired t-analysis.

FIG. 15 is a graph of the correlation of mean electrostatic measurementson the different metal surfaces presented in FIG. 14 with the polarcomponent of total metal surface energy; and total surface energy wascalculated by the harmonic method from surface contact anglemeasurements using water, formamide and xylene as the test liquids.

FIG. 16 is a graph showing significant correlation was observed betweenthe polar component of total surface energy and AFM measuredelectrostatic force.

FIG. 17 is a graph showing that electropolished Nitinol exhibits thelowest polar energy component of all four surfaces and, furthermore,that when its surface becomes heavily oxidized that the polar componentincreases almost 3-fold (from 1.3 to 3.4 dynes/cm), again, parallelingchanges observed in surface electrostatic force.

The foregoing and other features and advantages of the disclosure areapparent from the following detailed description of exemplaryembodiments, read in conjunction with the accompanying drawings; whereinlike structural or functional elements are designated by like referencenumerals.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with one embodiment, the capacity for completeendothelialization of conventional implantable materials, includingmetals and polymers, may be enhanced by imparting a pattern ofchemically and/or physiochemically active geometric physiologicallyfunctional features onto a blood contacting surface of the implantablematerial. The inventive implantable metal devices may be fabricated ofpolymers, pre-existing conventional wrought metallic materials, such asstainless steel or nitinol hypotubes, or may be fabricated by thin filmvacuum deposition techniques. In accordance with one embodiment, it ispreferable to fabricate the inventive implantable materials andresulting devices by vacuum deposition of either or both of the baseimplant material and the chemically and/or physiochemically activegeometric physiologically functional features. Vacuum deposition permitsgreater control over many material characteristics and properties of theresulting material and formed device. For example, vacuum depositionpermits control over grain size, grain phase, grain materialcomposition, bulk material composition, surface topography, mechanicalproperties, such as transition temperatures in the case of a shapememory alloy. Moreover, vacuum deposition processes will permit creationof devices with greater material purity without the introduction oflarge quantities of contaminants that adversely affect the material and,therefore, the mechanical and/or biological properties of the implanteddevice. Vacuum deposition techniques also lend themselves to fabricationof more complex devices than those that are manufactured by conventionalcold-working techniques. For example, multi-layer structures, complexgeometrical configurations, extremely fine control over materialtolerances, such as thickness or surface uniformity, are all advantagesof vacuum deposition processing. The embodiments disclosed herein to mayreplace polymer grafts with metal grafts that can potentially becomecovered with EC and can heal completely. Furthermore, heterogeneities ofmaterials in contact with blood flow are preferably controlled by usingvacuum deposited materials.

In vacuum deposition technologies, materials are formed directly in thedesired geometry, e.g., planar, tubular, etc. The common principle ofvacuum deposition processes is to take a material in a minimallyprocessed form, such as pellets or thick foils, known as the sourcematerial and atomize them. Atomization may be carried out using heat, asis the case in physical vapor deposition, or using the effect ofcollisional processes, as in the case of sputter deposition, forexample. In some forms of deposition a process such as laser ablation,which creates microparticles that typically consist of one or moreatoms, may replace atomization; the number of atoms per particle may bein the thousands or more. The atoms or particles of the source materialare then deposited on a substrate or mandrel to directly form thedesired object. In other deposition methodologies, chemical reactionsbetween ambient gas introduced into the vacuum chamber, i.e., the gassource, and the deposited atoms and/or particles are part of thedeposition process. The deposited material includes compound speciesthat are formed due to the reaction of the solid source and the gassource, such as in the case of chemical vapor deposition. In most cases,the deposited material is then either partially or completely removedfrom the substrate, to form the desired product.

A first advantage of vacuum deposition processing is that vacuumdeposition of the metallic and/or pseudometallic films permits tightprocess control and films may be deposited that have a regular,homogeneous atomic and molecular pattern of distribution along theirfluid-contacting surfaces. This avoids the marked variations in surfacecomposition, creating predictable oxidation and organic adsorptionpatterns and has predictable interactions with water, electrolytes,proteins and cells. In particular, EC migration is supported by ahomogeneous distribution of binding domains that serve as natural orimplanted cell attachment sites in order to promote unimpeded migrationand attachment.

Secondly, in addition to materials and devices that are made of a singlemetal or metal alloy layer, the inventive grafts may be comprised of alayer of biocompatible material or of a plurality of layers ofbiocompatible materials formed upon one another into a self-supportingmultilayer structure because multilayer structures increase themechanical strength of sheet materials, or to provide special qualitiesby including layers that have special properties such assuperelasticity, shape memory, radio-opacity, corrosion resistance etc.Vacuum deposition technologies may deposit layered materials and thusfilms possessing exceptional qualities may be produced. Layeredmaterials, such as superstructures or multilayers, are commonlydeposited to take advantage of some chemical, electronic, or opticalproperty of the material as a coating; a common example is anantireflective coating on an optical lens. Multilayers are also used inthe field of thin film fabrication to increase the mechanical propertiesof the thin film, specifically hardness and toughness.

Thirdly, the design possibilities for possible configurations andapplications of the inventive graft are greatly realized by employingvacuum deposition technologies. Specifically, vacuum deposition is anadditive technique that lends itself toward fabrication of substantiallyuniformly thin materials with potentially complex three dimensionalgeometries and structures that cannot be cost-effectively achieved, orin some cases achieved at all, by employing conventional wroughtfabrication techniques. Conventional wrought metal fabricationtechniques may entail smelting, hot working, cold working, heattreatment, high temperature annealing, precipitation annealing,grinding, ablation, wet etching, dry etching, cutting and welding. Allof these processing steps have disadvantages including contamination,material property degradation, ultimate achievable configurations,dimensions and tolerances, biocompatibility and cost. For exampleconventional wrought processes are not suitable for fabricating tubeshaving diameters greater than about 20 mm, nor are such processessuitable for fabricating materials having wall thicknesses down to about1 μm with sub-μm tolerances.

The embodiments disclosed herein takes advantage of the discoveredrelationship between chemically or physiochemically-active geometricphysiologically functional features defined and distributed on a bloodcontact surface and enhanced endothelial cell binding, proliferation andmigration over the blood contact surface of the implantable material.The embodiments disclosed herein involve focal adhesion point formationduring cellular movement and the anchorage dependence, that spreadingcells proliferate faster than non-spreading cells. The addition of apatterned array of geometric physiologically functional features, whichhave a hydrophobic, hydrophilic or surface energy difference relative tothe surface onto which the geometric physiologically functional featuresare added, enhances the binding, proliferation and migration ofendothelial cells to and between the geometric physiologicallyfunctional features and across the surface.

The geometric physiologically functional features disclosed herein maybe formed on, in, or through one or more layers of vacuum depositedbiocompatible material. In a first embodiment, the one or more layers ofvacuum deposited biocompatible material are deposited on a layer of bulkmaterial. In a second embodiment, a plurality of layers of vacuumdeposited biocompatible material is deposited on one another to form aself-supporting multilayer structure. Each of the first and secondembodiments includes several aspects. In a first aspect, the geometricphysiologically functional features may have a non-zero thicknesscorresponding to a thickness of one or more layers of the vacuumdeposited material. Alternatively, in other aspects, the geometricphysiologically functional features may have a zero thickness or athickness greater than one or more layers of the vacuum depositedmaterial.

Below about 3 μm in thickness, the interactions between endothelialcells and the geometric physiologically functional features areprimarily chemical and electrochemical. Geometric physiologicallyfunctional features having thicknesses greater than 3 μm and up to about20 μm may also be employed in the embodiments disclosed herein, it beingunderstood that as the thickness of the geometric physiologicallyfunctional feature increases there is a decreasing chemical and/orelectrochemical interaction between the geometric physiologicallyfunctional feature and the endothelial cells and an increasing physicalinteraction (topographic guidance effect).

Additionally, UV irradiation may be employed to oxidize titanium ortitanium-alloy surfaces, photochemical alteration of the surfacetitanium oxides alter the hydrophobicity of the exposed titanium oxidesand act as affinity binding and migration sites for endothelial cellattachment and proliferation across a titanium or titanium-alloysurface. Where UV irradiation is employed, the thickness of thephotochemically altered regions of titanium oxide are, for all practicalpurposes, 0 μm. Thus, within the context of the present application, theterm “geometric physiologically functional features” is intended toinclude both physical members and photochemically-altered regions havingthicknesses having thicknesses down to 0 μm.

In FIG. 1, a portion of an implantable material 10 showing the surfacematerial 12 with described elevated geometric physiologically functionalfeatures 14 is illustrated. The geometric physiologically functionalfeatures are elevated from the surface of the implantable material to aheight ranging from about 1 nm to about 20 μm. Preferably, the height ofthe geometric physiologically functional feature 14 ranges from about 1nm to about 3 μm. The shape of geometric physiologically functionalfeatures can be either circular, square, rectangle, triangle, parallellines, straight or curvilinear lines or any combination thereof. Each ofthe geometric physiologically functional features is preferably fromabout 1 nm to about 75 μm, and preferably from about 1 nm to 50 μm infeature width 16, or feature diameter if the geometric physiologicallyfunctional feature is circular. A gap distance 18 between each of thegeometric physiologically functional features may be less than, aboutequal to or greater than the feature width 16, i.e., between about 1 nmto about 75 μm edge-to-edge.

FIG. 2 is a cross-sectional view along line 2-2 in FIG. 1. One of theelevated geometric physiologically functional features 14 is shown onthe surface 12 of the implantable material.

In FIG. 3, a layer of a titanium or titanium-alloy material 20 isheating to oxidize and form titanium dioxide on the surface of thematerial 20. In one embodiment, the layer of titanium or titanium-alloymaterial 20 is deposited over one or more layers of vacuum depositedmaterial in a self-supporting multilayer structure. In anotherembodiment, the layer of titanium or titanium-alloy material 20 isdeposited over a bulk material that may have one or more layers ofvacuum deposited material deposited thereon.

The geometric physiologically functional features 24 are formed byexposing the layer of material 20 to UV through a pattern mask. UVirradiation alters the titanium oxides in the areas of geometricphysiologically functional features 24, thereby chemically altering thegeometric physiologically functional features 24 relative to thesurrounding the surrounding surface area 22 of material layer ofmaterial 20. The shape of geometric physiologically functional featurescan be circular, square, rectangle, triangle, parallel lines,intersecting lines or any combination. Each of the geometricphysiologically functional features is from about 1 nanometer to about75 μm, and preferably from about 1 nanometer to about 50 μm in featurewidth 16, or feature diameter if the geometric physiologicallyfunctional feature is circular. The gap distance 28 between eachcomponent of the geometric physiologically functional features may beless than, about equal to or greater than the feature width 26.

FIG. 4 is a cross-sectional view of FIG. 3 along line 4-4. The describedgeometric physiologically functional features 24 are indicated by thedotted lines, which indicate that the geometric physiologicallyfunctional features 24 are at the same level of the surrounding surface22.

FIG. 5 shows geometric physiologically functional features that areevenly distributed across the at least one surface of the implantablematerial that contacts body fluid, preferably blood. As disclosed inFIG. 1 and FIG. 2, the geometric physiologically functional features areelevated from the rest of the surface to a height ranging from about 1nanometer to about 20 micrometers. Preferably, the height of thegeometric physiologically functional feature ranges from about 1nanometer to about 3 micrometers. The shape of the geometricphysiologically functional features is not confined within the shapethat is shown. The shape of the chemically defined domain can also beany of circle, square, rectangle, and triangle, parallel lines,intersecting lines or any combination of the above.

FIG. 6A shows the cell 32 spreading on the surface of hydrophilictreated Si. FIG. 6B shows the cell 32 spreading on the surface ofhydrophilic treated Si with circular dots that are 15 microns indiameter. Cells in FIG. 6B appear to have much more focal adhesionpoints 36 than those in FIG. 6A. Because these geometric physiologicallyfunctional features provide for cell attachment, acting as affinitydomains, the size of each of these affinity domains relative to the sizeof an endothelial cell determines the availability of affinity domainsto the subsequent round of cell movement. According to one embodiment,the preferred size of each of the individual component of the geometricphysiologically functional features is about 1 nm to about 75 μm, andpreferably from about 1 nm to 50 μm in feature width, or diameter if thegeometric physiologically functional feature is circular. Focal adhesionpoint formation is the critical step in cell movement and cellproliferation; therefore, geometric physiologically functional featuressuch as carbon dots on the hydrophilic Si surface promote cell movement.Spreading of cells promotes cell proliferation, protein synthesis, andother cell metabolic functions. Promoting cell movement and cellproliferation ultimately accelerates covering of the implantedimplantable material with endothelial cells on exposed surfaces havingthe geometric physiologically functional features. Although thegeometric physiologically functional features shown in FIG. 6B arecircular, the shape of the geometric physiologically functional featuresare not limited to this particular embodiment.

FIG. 6C is a magnification of a portion of the image of FIG. 6B.Multiple focal adhesion points 36 are again shown. Wide spreading of thecell is primarily due to the formation of multiple focal adhesion pointson the circular geometric physiologically functional features. Extensivespreading of the cells is beneficial towards endothelialization becauseit promotes cell movement and cell proliferation.

FIG. 7 shows the stained focal adhesion points 36 of human aoticendothelial cells (HAEC) on the surface of an implantable material withgeometric physiologically functional features 14 that are in the form ofcarbon dots. The focal adhesion points are located at or very close tothe geometric physiologically functional features 14. These focaladhesion points serve as tension points for the cell to contract fromthe opposite end of the cell and hence promote cell movement.

FIG. 8A shows the wide spreading of cells 32 and focal multiple focaladhesion points 36 on the surface of an implantable material withgeometric physiologically functional features that are in the form ofNiTi dots of 25 micrometers in diameter. The NiTi dots are invisible dueto the weak contrast between the NiTi dots and surrounding Si surface.

FIG. 8B shows a magnified slide of a human aortic epithelial cell 32, asshown in FIG. 8A. Multiple focal adhesion points 36 are shown toencapsulate the NiTi dots patterned on the hydrophilic Si surface.

Referring to FIG. 9A, a portion of an implantable material 46 withsurface 42 and 44 is shown.

Referring to FIG. 9B, according to one embodiment, a machined mask 48having laser-cut holes 40 of defined size ranging from about 1 nm toabout 75 μm, and preferably from about 1 nm to 50 μm, patternedthroughout coats at least one surface 42 of the implantable material 46and is tightly adhered to the covered surface 42.

Referring to FIG. 9C, a thin film of material 14 was deposited into thespace as defined by the holes 40, as seen in FIG. 9B, in the mask 48 bythin film deposition procedures.

Referring to FIG. 9D, after deposition, the mask is removed to revealthe geometric physiologically functional features 49 patterned acrossthe at least one surface 42 of the implantable material 46.

As described above, the shape of the holes in the mask could be in anyof the shapes described for the geometric physiologically functionalfeatures including: circle, square, rectangle, triangle, parallel linesand intersecting lines, or any combination thereof. In the thin filmdeposition embodiment of the manufacturing the geometric physiologicallyfunctional features, the geometric physiologically functional featuresare elevated from the surface of the implantable material. The thicknessof the geometric physiologically functional features is based upon thethickness of the holes in the mask, the thickness ranging from about 1nm to about 20 micrometers. Preferably, the thickness of the holes inthe mask range from about 1 nm to about 3 micrometers.

The variations of geometric physiologically functional features may beadded to a surface of an implantable biocompatible material by vacuumdepositing a layer or layers of biocompatible material on the surface.In one embodiment, the geometry of the layer or layers of depositedmaterial defines the geometric physiologically functional features. Forexample, an implantable material 100 has a surface 104, as illustratedin FIG. 11A. In one embodiment, the implantable biocompatible materialmay comprise one or more layers 102 of vacuum deposited material formedinto a self-supporting structure, as illustrated by FIG. 11A showing afirst layer 102 a, a second layer 102 b, a third layer 102 c, a fourthlayer 102 d, and a fifth layer 102 e. In another embodiment, theimplantable biocompatible material includes a bulk material, either abulk material alone or a bulk material covered by the one or more layers102 a-102 e of vacuum deposited biocompatible material. Five layers 102a-102 e of vacuum deposited material are illustrated; however, anynumber of layers may be included as desired or appropriate.

The one or more layers 102, may have thicknesses that are the same ordifferent as desired or appropriate. Each layer may have a thickness ina range from about 1 nanometer to about 20 micrometers, from about 1nanometer to about 10 micrometers, from about 1 nanometer to about 5micrometers, or from about 1 nanometer to about 3 micrometers.Alternating layers 102 of varying thicknesses may be applied as toaccommodate the geometric physiologically functional features.

In this embodiment, the geometric physiologically functional featuresmay be added to the surface 104 by adding one or more layers 102 ofvacuum deposited material. For example, referring to FIGS. 11B-11E, inone process, a mask 106 having holes 108 of defined size disposedtherethrough and patterned throughout coats and is tightly adhered to atleast a first portion of the surface 104. The holes 108 may be cutthrough the mask 106, for example, by using a laser, wet or dry chemicaletching, or other like methods for forming holes through a material, orthe mask 106 may be fabricated including the holes 108. The thickness ofthe holes 108 may range about 1 nanometer to about 20 micrometers, fromabout 1 nanometer to about 10 micrometers, from about 1 nanometer toabout 5 micrometers, or from about 1 nanometer to about 3 micrometers.

The shape of the holes 108 as seen in FIG. 11C or as looking in thedirection of arrow 110 may be any of the shapes described for thegeometric physiologically functional features including: circle, square,rectangle, triangle, polygonal, hexagonal, octagonal, elliptical,parallel lines and intersecting lines, or any combination thereof. Theholes 108 may have a width 112, or diameter 112 if the holes arecircular, in a range between about 1 nanometer and about 75 micrometers,between about 1 nanometer and about 50 micrometers, between about 1nanometer and about 2000 nanometers, or between about 1 nanometer andabout 200 nanometers. Adjacent holes 108 may be spaced apart by adistance D in a range from about 1 nanometer to about 20 micrometers,from about 1 nanometer to about 10 micrometers, from about 1 nanometerto about 5 micrometers, or from about 1 nanometer to about 3micrometers. The distance D may be less than, about equal to or greaterthan the width 112. In another embodiment (not shown), the width 112 ofeach of the holes 108 and/or the distance D between adjacent holes 108may vary in size to form a patterned array of the holes 108.

Referring to FIG. 11D, a layer 114 of material was deposited into aspace as defined by the holes 108 in the mask 106 by vacuum deposition.The layer 114 has a thickness essentially the same as that of the mask106. In some embodiments, the thickness of the mask may be variableacross the mask 106. After removal of the mask 106, geometricphysiologically functional features 116 are revealed patterned acrossthe surface 104 of the implantable material 100. Each of the geometricphysiologically functional features 116 includes a top surface 118. Eachof the geometric physiologically functional features 116 has dimensionsas described hereinabove for the holes 108 in the mask 106.

In another embodiment where geometry of the layer or layers of depositedmaterial defines the geometric physiologically functional features, apatterned array of recesses may be formed each having a hydrophobic,hydrophilic or surface energy difference relative to the surface intowhich the recesses are added, meaning a top most surface of thedeposited layers, the difference enhancing the binding, proliferationand migration of endothelial cells to and between the recesses andacross the surfaces, recessed and top most. The hydrophobic, hydrophilicor surface energy differences relative to the surface may be formed, byway of example, any of the methods disclosed in commonly assigned U.S.patent application Ser. No. 12/428,981, filed Apr. 23, 2009,incorporated by reference herein.

In this embodiment, the recesses may be formed by a relative lack ofdeposition of a layer or layers onto a surface, or by machining recessesthrough a layer or layers of material vacuum deposited on a surface. Forexample, to produce a pattern of recesses similar to the pattern ofgeometric physiologically functional features 116 illustrated in FIG.11E, in one example, a process begins by executing the steps describedhereinabove with regard to FIGS. 11A-11E, to produce the pattern ofgeometric physiologically functional features 116 illustrated in FIG.11E, except in this embodiment, the layer 114 of material is asacrificial layer of material that is removed in a subsequent step.

Referring to FIGS. 12A and 12B, a layer 120 of material is depositedinto spaces between the geometric physiologically functional features116 by vacuum deposition. The layer 120 has a thickness essentially thesame as that of the geometric physiologically functional features 116.In this embodiment, after vacuum deposition of the layer 120, thegeometric physiologically functional features 116 of the sacrificiallayer 114 are removed, for example, by chemical etching, photo etching,laser ablation, or other method reveal geometric physiologicallyfunctional features 122 patterned across the surface 104 of theimplantable material 100. Each of the geometric physiologicallyfunctional features 122 is a recess that has a thickness or depthbetween a surface 124 of the layer 120 and the surface 104.

The shape of the recesses 122 as seen looking in the direction of arrow126 in FIG. 12B may be any of the shapes described for the geometricphysiologically functional features including: circle, square,rectangle, triangle, polygonal, hexagonal, octagonal, elliptical,parallel lines and intersecting lines, or any combination thereof. Therecesses 122 may have the width 112, or diameter if the recesses 122 arecircular, in a range between about 1 nanometer and about 75 micrometers,alternatively between about 1 nanometer and about 50 micrometers,alternatively between about 1 nanometer and about 2000 nanometers, oralternatively between about 1 nanometer and about 200 nanometers.Adjacent recesses 122 may be spaced apart by the distance D in a rangefrom about 1 nanometer to about 20 micrometers, from about 1 nanometerto about 10 micrometers, from about 1 nanometer to about 5 micrometers,or from about 1 nanometer to about 3 micrometers. The distance D may beless than, about equal to or greater than the width 112. In anotherembodiment (not shown), the width 112 of each of the recesses 122 and/orthe distance D between adjacent recesses 122 may vary in size to form apatterned array of the recesses 122.

In another embodiment, the recesses 122 having width and spacing asdescribed hereinabove with regard to FIGS. 12A and 12B may be formed bymachining the recesses 122 through a layer or layers 128 of vacuumdeposited material. For example, an implantable material 130 having asurface 132, may comprise a bulk material 134, the one or more layers128 of vacuum deposited material, or the bulk material 134 and the oneor more layers 128 of vacuum deposited material, as illustrated in FIG.13A.

Alternatively, as shown in FIG. 12C, the geometric physiologicallyfunctional features 116 themselves include a plurality of depositedlayers, wherein the geometric physiologically functional features 116include the first layer 102 a, the second layer 102 b, and the thirdlayer 102 c. The geometric physiologically functional features 116 aredeposited through a mask as previously indicated, on top of structuralmaterial of the stent or other medical device include deposited layer102 d and 102 e. Alternatively, the geometric physiologically functionalfeatures 116 include the first layer 102 a and the second layer 102 b,deposited through the mask whereby the structural material of the stentor other medical device includes the layers 102 c-102 d. Alternatively,the geometric physiologically functional features 116 include the firstlayer 102 a, the second layer 102 b, the third layer 102 c, and thefourth layer 102 d, whereby the structural material of the stent orother medical device includes the fifth layer 102 e. When additionallayers 102 a-102 d are included in the geometric physiologicallyfunctional feature 116, the thickness of the layers as deposited can bemodified to be a narrower or decreased thickness as to allow for thegeometric physiologically functional feature 116 to be adjusted to aparticular thickness. The layers of different vacuum deposited materialscan be deposited to create the elevated surfaces having inherentlydifferent material properties. Alternatively, layers of the same vacuumdeposited material can be deposited having differences in grain size,grain phase, and/or surface topography or variations of hydrophobic,hydrophilic or surface energy difference relative to the surface of thestent or structural material. The grain size, grain phase, and/orsurface topography or variations of hydrophobic, hydrophilic or surfaceenergy difference relative to the surface of the stent or structuralmaterial may be formed or included on the surface as shown in U.S.patent application Ser. No. 12/428,981, which was filed Apr. 23, 2009,incorporated by reference herein.

Alternatively, as shown in FIG. 12D, the recesses 122 may include aplurality of layers 102 to provide for differences in grain size, grainphase, and/or surface topography or variations of hydrophobic,hydrophilic or surface energy difference relative to the surface of thestent or structural material. The recesses 122 may be formed by thesurface 124 being deposited through a mask as to form the layer 120 thatgives rise to the plurality of recesses 122 with a wall 123. As such,the recesses 122 include an inner wall 123 including the first layer 102a, the second layer 102 b, and the third layer 102 c, whereby thesurface 104 is on layer 102 d, which is exposed on the bottom of therecess 122 and surface 124 is on top of layer 102 a. Alternatively, therecesses 122 may include a wall of the first layer 102 a and the secondlayer 102 b, whereby the surfaces 124 are deposited through a mask, andthe structural material of the stent or other medical device includesthe layers 102 d-102 e. Alternatively, the recesses 122 include a wallof the first layer 102 a, the second layer 102 b, the third layer 102 c,and the fourth layer 102 d, and surfaces 124 are deposited through amask whereby surface 102 e that acts as the surface 104 of thestructural material of the medical device. When additional layers 102a-102 d are included as the wall in the geometric physiologicallyfunctional feature 116, the thickness of the layers as deposited can bemodified to be a narrower or decreased thickness as to allow for thegeometric physiologically functional feature 116 to be adjusted to aparticular thickness. The layers of different vacuum deposited materialscan be deposited to create recesses having inherently different materialproperties. Alternatively, layers of the same vacuum deposited materialcan be deposited having differences in grain size, grain phase, and/orsurface topography or variations of hydrophobic, hydrophilic or surfaceenergy difference relative to the surface of the stent or structuralmaterial.

Referring to FIG. 13B, recesses 136 may be machined into the surface 132of the implantable material 130 to have a depth greater than a thicknessof a first layer of material 128 a or recesses 138 may be machined intothe surface 132 of the implantable material 130 to have a depth greaterthan a thickness of the first and second layers 128 a, 128 b ofmaterial. Two layers are illustrated for convenience of explanation andillustration; however, any number of layers 128 of material may be usedas desired or appropriate. In this embodiment, each of the recesses 136has a thickness or depth between the surface 132 of the layer 128 a anda surface 140 that is within a second layer 128 b. Similarly, each ofthe recesses 138 has a thickness or depth between the surface 132 of thelayer 128 a and a surface 142 that is within the bulk material 134.

An implantable material including geometric physiologically functionalfeatures comprising a layer or layers of vacuum deposited material, asillustrated by the geometric physiologically functional features 116 inFIG. 11E, recesses disposed through one or more layers of vacuumdeposited material, as illustrated by the recesses 122 in FIG. 12B orthe recesses 136 or 138 in FIG. 13B, has an inherently differentstructure than a block of material having recesses cut into it. Thereason for this inherent difference lies in the differences in thematerials making up surfaces exposed by the recesses. For example, inthe case of a block of material and assuming that the block material isuniform in regard to material properties, an undisturbed surface of theblock and a surface within a recess or groove cut into the block havethe same material properties.

In contrast, layers of different vacuum deposited materials can bedeposited to create recessed and/or elevated surfaces having inherentlydifferent material properties. In fact, layers of the same vacuumdeposited material can be deposited having differences in grain size,grain phase, and/or surface topography. The alternative grain size,grain phase, and/or surface topography may be included or formed, by wayof example, any of the methods disclosed in commonly assigned U.S.patent application Ser. No. 12/428,981, filed Apr. 23, 2009,incorporated by reference herein. For example, surfaces of the recesses122, 136 can be deposited to have a roughened surface topography and alarge grain size and surfaces of the material deposited defining therecesses 122, 136, for example the layer 120 illustrated in FIG. 12B,can have a relatively smoother surface topography and/or a smaller grainsize. Alternative grain sizes and surfaces may be formed and included asshown in U.S. patent application Ser. No. 12/428,981, which was filedApr. 23, 2009, previously incorporated by reference.

It is contemplated that a factor in increasing endothelialization of asurface of an implanted medical device may be the cleanliness of thesurface. In this context, cleanliness refers to the presence or lack ofcontaminant molecules bonding to otherwise unsaturated chemical bonds atthe surface. A perfectly clean surface, for example as may exist in avacuum, comprises unsaturated bonds at the surface that have not boundto any contaminant molecules. The unsaturated bonds provide the surfacewith a higher surface energy as compared to a contaminated surfacehaving fewer unsaturated bonds, which have a lower surface energy.Measurements of surface energy may be accomplished by contact anglemeasurements, as disclosed in U.S. patent application Ser. No.12/428,981, which was filed Apr. 23, 2009.

Unfortunately, unsaturated chemical bonds at the surface will bond tocontaminant molecules when exposed thereto. For example, there are manyair-borne chemistries such as phthalates, hydrocarbons, and even waterthat may bond to unsaturated bonds or otherwise attach to reactive spotssuch as, for example, residual negative charges on the surface of ametal oxide. Such contaminant molecules, for example, normally occurringhydrocarbons, SO₂, NO, etc., occupy otherwise unsaturated bonds therebyreducing the number of unsaturated bonds and lowering the surface energyof the surface. Such reduction in the number of unsaturated bondsdecreases the availability of such unsaturated bonds for interactionwith blood proteins.

The air atmosphere around the surface include normally occurringimpurities which will be attracted to the unsaturated chemical bonds atlevels in the air around 1×109 to 1×106 so it will take a few secondsbefore the surface is contaminated by their Brownian motion, after 1min, most of the unsaturated bond are saturated with contaminants. Onemolecular monolayer (i.e. a single layer of molecules) will be adsorbedon the surface. On longer time scales, additional molecules may bond tothe surface and build multi-layers of contaminant molecules. The surfaceof a few molecular monolayers of contaminants may have thickness ofabout 0.1-2 nm, which may be detected by sensitive surface analysis asindicated above.

Thus, as relates to endothelialization, a cleaner surface having moreunsaturated bonds provides increased potential for interaction withblood proteins. It is contemplated that a contaminated surface of avacuum deposited or bulk material can be activated, or made more likelyto interact with blood proteins, by removing the contaminant moleculesthat occupy the otherwise unsaturated bonds at the surface. There may beseveral techniques for accomplishing such activation, including by wayof example and not limitation, chemical etching, wet chemical etching,oxidation, electrochemical treatment, thermal treatment, UV-ozonecleaning, coating by evaporation or sputtering, etc. For example,another technique for activating a vacuum deposited surface may be byusing plasma electron bombardment under vacuum, a technique also knownas plasma etching. The contaminant layer may be detected bysurface-sensitive spectrosscopies, such as Auger electron spectroscopy(AES), x-ray photoemission spectroscopy (XPS or ESC), infraredreflection absorption spectroscopy (IRAS, FT-IR, etc.) secondary ionmass spectroscopy (SIMS), and those disclosed in U.S. patent applicationSer. No. 12/428,981.

Plasma etching the sample to be treated is positioned within acontrolled electrical gas discharge (a plasma). The plasma may be formedby applying a high voltage (AC or DC) over a gas under considerablylower pressure than one atmosphere (typically 0.1-1 mm Hg, or a vacuum).Because of the low pressure and because gas purity is vital for theprocess, the discharge and the sample must be housed in a hermeticallyclosed system that can be evacuated by vacuum pumps, and whose gascomposition can be controlled. The plasma also has sufficient energy andmomentum to remove atoms and molecules that are adsorbed on unsaturatedbonds, or are constituents of the native surface. As such, thecontamination layer bond to unsaturated bonds may be removed, torecreate the unsaturated bonds on the surface and thus increasing thesurface energy. Depending on the parameters of the discharge (gaspressure and composition, applied voltage, current density, position ofthe sample, etc.) the surface treatment can be mild (mainly removal ofthe contamination layer) or more aggressive. The complete surface oxidelayer on a metal may be removed so that the bare metal is exposed. Thelatter occurs only provided that no oxidizing or other reactive gasesare present, i.e., the used gas must be a noble gas such as Ar, Kr, orXe. By controlling the gas atmosphere, the composition of the newlyformed surface is controlled; if oxygen is added, oxide will be formed;if nitrogen or hydrocarbons are added, surface nitride or surfacecarbide, respectively, will form, etc. The gas purity must be high, asimpurities within the gas will react to the high energy cleanedsurfaces.

Because of the omnipresence of contaminant molecules in the environment,a surface once activated may not remain activated until implantationinto a patient. Thus, an important consideration of the activationprocess is how to preserve the activated surface long enough to providethe benefit of activation upon implantation. In this context, theactivated surface may be preserved by introducing a contaminant gas orliquid into the plasma etching process in a controlled manner, which maybe easily removed before use of the medical device. The contaminantlayer may be a known biodegradable material or may be a contaminantlayer or coating of inorganic or organic nature or a mixture of both.For example, the contaminant layer may be layer readily removed by asaline or water solution, which are typically used in flushingprocedures or washing procedures.

Alternatively, the activated surface may be coated with a protectivecoating, for example, a biodegradable material that dissolves uponexposure to the in vivo environment when implanted. The biodegradablematerial may alternatively be dissolved via introduction of anexternally delivered fluid solvent during implantation. Alternatively,the protective coating may be a fluid in which the activated device isimmersed until implantation. For example, it is contemplated thatstoring the activated surface in water facilitates preservation of theactivation as compared to exposure of the activated surface to air. Thebiodegradable material may be any material, natural or synthetic, thatmay be broken down by living organisms, including, but not limited to abiodegradable organic substance, biodegradable polymer substances(Poly(lactic acid) PLA, poly(L-lactic acid) (PLLA),poly(lactic-co-glycolic acid) PLGA, poly(glycolicacid) (PGA),Polyethylene glycol, PEG, polytetrafluoroethylene (PTFE), and the like),peptides or proteins, carbohydrates, nucleic acids, fatty acids,carbon-containing compounds, nanoparticles, microparticles,biocomposites, sol-gel coatings, hydrogels water-soluble bioactive agentand poly(alkyl cyanoacrylate) polymer coating; nanoparticle coatingformed by electrospraying; a poly(diol citrates)-based coatings; naturalbiodegradable hydrophobic polysaccharides coatings, hydrophilicpolymers, and the like. Alternatively, other materials may be used, suchas gold, other metals, heparin, silicon carbide, titanium-nitride-oxide,phoshphorylcholine, and other medical device coatings.

The method disclosed herein comprehends the creation of a patternedarray of geometric physiologically functional features elevated relativeto a surface of an implantable biocompatible material, recessed relativeto the surface, or disposed on the surface. For example, in accordancewith an alternative embodiment, the implantable biocompatible materialis formed of a bulk material of titanium, nickel-titanium alloy or othertitanium-rich alloy metals or a top most layer of titanium,nickel-titanium alloy or other titanium-rich alloy metals deposited overthe bulk material. The titanium, nickel-titanium alloy or othertitanium-rich alloy metal is oxidized to convert surface titanium totitanium dioxide, then covered with a pattern-mask and exposed to highintensity UV irradiation. It is well-known that titanium dioxide (TiO₂)absorbs UV radiation and has been used in a variety of applications as aUV inhibitor to prevent UV transmission across a TiO₂ barrier layer. Ithas been discovered that upon exposure to UV irradiation, an originallyhydrophobic and oleophilic titanium oxide layer becomes amphiphilic.

The effect of UV irradiation on a titanium oxide surface is believed tooccur because of unsymmetrical cleavage of the Ti—O bond to leave Ti³⁺ions on the surface in some regions. Presently, these amphiphilicsurfaces are being used in a range of technological applications, suchas self-cleaning paints and anti-misting glasses. It has been recognizedthat these amphiphilic titanium oxide layers have use in medicalapplications. Zarbakhsh, A., Characterization of photon-controlledtitanium oxide surfaces, ISIS Experimental Report, Rutherford AppeltonLaboratory, May 16, 2000 (which may be found on the internet at:www.isis.r1.ac.uk/isis2001/reports/11144.pdf).

The amphiphilic state of the UV irradiated titanium oxide may beadvantageously employed as an alternative to depositing patternedelevated or recessed geometric physiologically functional features ontothe implantable biocompatible material. An implantable biocompatiblematerial fabricated having a bulk substrate or a top most vacuumdeposited layer of titanium or a titanium alloy is masked with a patternmask having a plurality of openings passing there through. As with theabove-described embodiment, the plurality of openings preferably have asize and special array selected to define affinity binding domains andcellular migration cites for promoting endothelial cell binding andproliferation across the substrate surface.

The open surface area of each of the plurality of openings in thepattern mask is preferably in the range of between about 1 nm to about75 μm, and with adjacent pairs of openings being in a spaced apartrelationship such that a distance of about 1 nm to about 75 μm existsbetween the openings, the inter-opening being greater than, about equalto, or less than the size of the opening. By interposing the patternmask between a UV source and the surface of the implantablebiocompatible material, a pattern of UV irradiated regions is impartedto the surface implantable biocompatible material, thereby altering thetitanium dioxides present at the irradiated regions and forming affinitydomains at the surface implantable biocompatible material.

Referring to FIG. 10A, a portion of an implantable material 56 made oftitanium or a titanium-alloy is shown having at least one surface 52 and54 that is oxidized by heating or an equivalent known by the personskilled in the art.

Referring to FIG. 10B, according to one embodiment, a machined mask 48that had laser-cut holes 40 of defined size from about 1 nm to about 75μm, from about 1 nm to about 50 μm, from about 1 nm to about 2000 nm,and preferably from about 1 nm to about 200 nm, patterned throughout tocoat the at least one surface 52 of the implantable material 56 and istightly adhered to the covered surface 52.

Referring to FIG. 10C, the implantable material 56 covered with the mask48 is then illuminated by the ultraviolet rays. Because TiO₂ issensitive to ultraviolet, the chemical composition in holes 58 isdifferent from the area that is covered by the mask. In contrast to thegeometric physiologically functional features illustrated in FIGS. 9C,11E, 12B, and 13B, the geometric physiologically functional features 59in FIG. 10C are not elevated and therefore have zero thickness relativeto the surrounding surface of the implantable material.

Referring to FIG. 10D, after ultraviolet irradiation, the mask isremoved to reveal the surface 52 that surrounds the geometricphysiologically functional features 59 formed by ultravioletirradiation. As described above, because the shape of the holes 58 inthe mask 48 could be in any of the shapes described for the geometricphysiologically functional features including: circle, square,rectangle, triangle, parallel lines and intersecting lines, andcombinations thereof, the geometric physiologically functional features58 accordingly adopts such shapes also.

Example 1

Nickel-titanium sheets were heated to oxidize titanium present at thesurface of the sheet. Pattern masks fabricated from machined metal werelaser drilled a pattern of holes having diameters ranging from 15 μm to50 μm, with a single diameter of holes on each pattern mask. A singlepattern mask was placed over a single nickel-titanium sheet and theassembly was exposed to high intensity ultra-violet irradiation. AfterUV irradiation, the irradiated nickel-titanium sheet was placed on afully endothelialized test surface and maintained at 37° C. undersimulated in vivo flow conditions and under static flow conditions.Qualitative observations were periodically made and it was found thatendothelial cells bound to the pattern of UV irradiated affinity domainsand migrated across the nickel-titanium sheet by proliferating acrossthe pattern of affinity domains, eventually fully seeding endothelium onthe nickel-titanium sheet.

Example 2

Selected metal pieces (Flat, 1×1 cm square pieces ( 1/16 in. thick) ofelectropolished 316L stainless steel, electropolished and heat-treated,electropolished Nitinol, gold and titanium) were subjected toradiofrequency plasma glow discharge using an EMS-100 glow dischargeunit (Electron Microscopy Services, Fort Washington, Pa.). For thisprocedure, the flat metal piece is placed on a flat metal platformwithin the glow discharge vacuum chamber. The plasma treatments wereconducted at a base vacuum pressure of 10-2 mbar in the presence of apurified argon gas atmosphere. The sample was always at negativepotential as the cathode using an applied current of 20 mamps for thetreatment time of 3 min. Under these conditions the surface of thesample is bombarded with argon ions resulting in the removal of surfaceoils and other surface contaminating molecules. Electrostatic forceanalyses were performed on these samples within 2 hr after removal fromglow discharge treatment.

For calculation of metal surface energy values, contact anglemeasurements were performed using a VCA-2500XE video contact anglesystem (AST systems, Billerica, Mass.) on the flat metal pieces aftercleaning as described above. The surface energy of all materials studiedwas determined by the advancing contact angle measurement of threestandard liquids; water, formamide and xylene; on each metal surface andcalculated by the harmonic mean method. Ten videocaptures per second ofthe advancing fluid droplet/solid interface were obtained for water andformamide and 65 captures per second for xylene. All experiments wererepeated 4 times.

Glow discharge plasma treatment is often used as a method of cleaningand removing surface contaminants from metallic as well as othersurfaces. Glow discharge treatment of many metallic surfaces causestheir surfaces to change from very hydrophobic surfaces on which waterbeads to a hydrophilic surface on which water rapidly spreads. This canbe quantitatively measured using contact angle measurement techniques,described above. In the case of stainless steel, a change in watercontact angle was measured from 98° prior to treatment to 7° after glowdischarge. With this profound alteration in surface characteristicsassociated with glow discharge treatment, it was important to examinewhether these physical alterations in surface behavior might beassociated with an alteration in surface electrostatic forces. Gold,stainless steel and electropolished Nitinol all exhibit net attractiveforces subsequent to glow discharge treatment, as shown in FIG. 14.Nitinol and gold now exhibit highly attractive forces that aresignificantly higher (p<0.001) than that observed on stainless steel.

It is likely based upon the profound change in measured surfaceelectrostatic energy associated with glow discharge treatment and asimilar dramatic change in water contact angle measurements that the twoapproaches to surface characteristics might be fundamentally related. Tofully explore this possibility, contact angles on gold, stainless steel,electropolished Nitinol, and heat-treated oxidized Nitinol were measuredusing water, xylene, and formamide. Using the Harmonic Mean method,these measurements were used to calculate the total surface energyassociated with each of the metallic surfaces. The final total surfaceenergy value represents the sum of the polar and hydrophobic dispersiveforces. To evaluate a possible association with these components oftotal surface energy to AFM measured electrostatic forces, the possiblecorrelations between electrostatic force and either total surface energywere examined, the polar component of surface energy or the dispersivecomponent. As demonstrated in FIG. 16, a significant correlation wasobserved between the polar component of total surface energy and AFMmeasured electrostatic force. Within this comparison it is noteworthythat electropolished Nitinol exhibits the lowest polar energy componentof all four surfaces and, furthermore, that when its surface becomesheavily oxidized that the polar component increases almost 3-fold (from1.3 to 3.4 dynes/cm), again, paralleling changes observed in surfaceelectrostatic force (FIG. 17).

While the present invention has been described with reference to itspreferred embodiments, those of ordinary skill in the art willunderstand and appreciate that variations in materials, dimensions,geometries, and fabrication methods may be or become known in the art,yet still remain within the scope of the present invention which islimited only by the claims appended hereto. It is understood, therefore,that this disclosure is not limited to the particular embodimentsdisclosed, but it is intended to cover modifications that may include acombination of features illustrated in one or more embodiments withfeatures illustrated in any other embodiments. Various modifications,equivalent processes, as well as numerous structures to which thepresent disclosure may be applicable will be readily apparent to thoseof skill in the art to which the present disclosure is directed uponreview of the present specification. Accordingly, this description is tobe construed as illustrative only and is presented for the purpose ofenabling those skilled in the art to make and use the implantablematerials having engineered surfaces described herein and to teach thebest mode of carrying out the same.

I claim:
 1. A method for making an implantable, biocompatible material,comprising the steps of: a. providing an implantable, biocompatiblematerial having at least one surface intended to contact tissue and bodyfluids in vivo; b. providing a mask having a defined pattern of openingscorresponding in size and spacing to a predetermined distribution ofendothelial cell binding domains to be imparted to the at least onesurface; c. treating the at least one surface of the biocompatiblematerial through the mask by at least one of: i. vacuum depositing alayer of material onto the at least one surface, wherein the vacuumdeposited layer is different from the at least one surface immediatelytherebeneath in a material property selected from the group of materialproperties consisting of: grain size, grain phase, grain materialcomposition, surface topography, and transition temperature, andremoving the mask to yield a plurality of binding domains defined on theat least one surface of the implantable, biocompatible material; and ii.vacuum depositing a layer of sacrificial material onto the at least onesurface, removing the mask from the at least one surface, vacuumdepositing a second layer of material onto the at least one surface,wherein the second vacuum deposited layer is different from the at leastone surface immediately therebeneath in a material property selectedfrom the group of material properties consisting of: grain size, grainphase, grain material composition, surface topography, and transitiontemperature, and removing the sacrificial material to yield a pluralityof binding domains defined on the at least one surface of theimplantable, biocompatible material.
 2. The method of claim 1, whereinthe implantable, biocompatible material in the providing step comprisesa bulk material.
 3. The method of claim 1, wherein the implantable,biocompatible material in the providing step comprises one or morelayers of vacuum deposited biocompatible materials.
 4. The method ofclaim 1, wherein a gap distance measured between immediately adjacentopenings in the mask measures between about 1 nanometer and about 2000nanometers, wherein the gap distance measures about the same as a widthof each of the openings, and wherein the mask has a thickness betweenabout 1 nm and about 3 μm.
 5. The method of claim 1, further includingthe step of activating the at least one surface of the implantable,biocompatible material by removing contaminant molecules that occupyotherwise unsaturated bonds at the at least one surface.
 6. The methodof claim 5, wherein the activating step further comprises activating theat least one surface of the implantable, biocompatible material by atechnique for activation selected from the techniques for activation ofthe at least one surface consisting of: chemical etching,electrochemical treatment, thermal treatment, and plasma etching.
 7. Themethod of claim 5, further including the step of preserving theactivation of the at least one surface prior to implantation.
 8. Themethod of claim 7, wherein the preserving step further includes coatingthe activated at least one surface subsequent to activation thereof witha biodegradable material that dissolves upon exposure to an in vivoenvironment.
 9. The method of claim 7, wherein the preserving stepfurther includes coating the activated at least one surface subsequentto activation thereof with a biodegradable material.